Project Summary/Abstract Systemic lupus erythematosus (SLE) is characterized by a variety of clinical and immunological manifestations. This proposal focuses on an animal model of lupus, pristane-induced lupus, which recapitulates many of the key features of human SLE including impaired phagocytosis of dead cells and their recognition by receptors of the innate immune system such as toll-like receptor 7 (TLR7). TLR7-stimulated proinflammatory cytokine production plays an important role in autoantibody production, nephritis, arthritis, and the hematological manifestations of lupus. However, preliminary studies suggest that diffuse alveolar hemorrhage (DAH) is TLR and cytokine independent and also independent of inflammasomes, suggesting that novel mechanisms are involved in lung inflammation. The long-term objective is to define the abnormal immunological pathways responsible for the clinical features of SLE. The central hypothesis is that lupus in pristane-treated mice and SLE patients is caused by impaired/altered phagocytosis of apoptotic cells, leading to inappropriate activation of several inflammatory pathways, which precipitate various aspects of the clinical syndrome. Three Specific Aims are proposed: Aim 1 addresses the mechanism of inflammation in DAH, examining the contribution of monocyte/macrophage subsets to the pathogenesis of lung inflammation. Aim 2 addresses how pristane impairs the phagocytosis of dead cells by macrophages, leading to chronic inflammation instead of the normal anti-inflammatory response. Aim 3 examines the relevance of pristane-induced lupus to the pathogenesis of inflammation and DAH in lupus patients. Taken together, these Aims will provide a more complete picture of why apoptotic cells are removed inefficiently in SLE patients and how this promotes chronic inflammation, autoimmunity, and tissue damage. Delineating the signaling pathways activated when dead cells are recognized by different macrophage subsets may suggest approaches to correct the phagocytic defect in SLE and/or treat its consequences. In particular, these studies may lead to new strategies for treating DAH, a complication of lupus that is fatal in over 50% of patients.